PTH-related peptide (PTHrP) is a causative agent of hypercalcemia associated with malignancy. PTHrP binds to and activates the same receptor as does PTH. Because PTHrP has been suggested to regulate the growth and differentiation of cells as a paracrine/autocrine factor, we examined the expression of both PTHrP and its receptor genes during fetal development of rats (15-20 days gestation) by in situ hybridization with riboprobes. Both PTHrP and its receptor messenger RNAs (mRNAs) were expressed not only in the skeleton, but also in many fetal extraskeletal tissues, such as choroid plexus, ears, lungs, tooth buds, heart, and skin. In these extraskeletal tissues PTHrP mRNA was expressed mainly in surface-lining cells, whereas its receptor mRNA was expressed mainly in adjacent mesenchyma cells. In endochondral bones, these two genes were expressed in largely discrete, but mostly neighboring, areas, although the localizations of these two mRNAs changed over developmental stages. The expression patterns of PTHrP and its receptor mRNAs during fetal development suggest PTHrP's roles as a paracrine factor and its involvement in epithelial-mesenchymal(-like) interactions.